Utility of Optical Genome Mapping for Accurate Detection and Fine-Mapping of Structural Variants in Elusive Rare Diseases

Autores de IIS La Fe

• Carmen Orellana Alonso

  Autor

• Laia Pedrola Vidal

  Autor

• Carla Martín Grau

  Autor

• Alba Gabaldon Albero

  Autor

• María Leonor Senent Peris

  Autor

• Esperanza Such Taboada

  Autor

• Cristian García Ruiz

  Autor

• Gayane Avetisyan

  Autor

• 

  Francisco Martínez Castellano

  Autor

Participantes ajenos a IIS La Fe

• Rosello, M
• Sanchis, A

Grupos

• Hematología y Hemoterapia

• Investigación Traslacional en Genética

Abstract

Rare diseases (RDs) often have a genetic basis, yet conventional diagnostic techniques fail to identify causative genetic variations in up to 50% of cases. Structural variants (SVs), including balanced rearrangements, frequently evade detection by karyotyping, microarray, and exome sequencing. The present study utilized optical genome mapping (OGM) to investigate two patients with RDs whose genetic etiology remained unresolved despite prior genomic analyses. Patient 1 exhibited a balanced reciprocal translocation disrupting the BCL11A gene, associated with Dias-Logan syndrome. Patient 2 had a mosaic 682 kb deletion near the IHH gene, causing ectopic enhancer-promoter interactions and polydactyly, mirroring phenotypes observed in mouse models and similar human cases. These findings highlight OGM's efficacy in identifying complex SVs and underline novel pathogenic mechanisms in rare genetic disorders. Consequently, the incorporation of OGM into routine diagnostic procedures will enhance genetic diagnosis, discover new syndromes of currently unknown cause, and eventually improve the clinical management of numerous patients with rare diseases.

Keywords

• optical genome mapping; structural variants; balanced translocation; enhancer-promoter interactions; congenital malformations; IHH; BCL11A